Despite the ability of antiretroviral therapy to minimize human immunodeficiency virus type (HIV) replication and increase the duration and quality of patients' lives, the health consequences and financial burden associated with the lifelong treatment regimen render a permanent cure highly attractive. Although T cells play an important role in controlling virus replication, they are themselves targets of HIV-mediated destruction.
Restoration of CD4 T cell activity, whether by immune augmentation or by protection from deletion, is a critical factor to enable long-term control of HIV replication in the absence of highly active antiretroviral therapy (HAART). Attempts to manufacture T cells as therapeutic agents to treat HW have been ongoing for over two decades. T cells can be engineered to express a synthetic immunoreceptor comprised of an extracellular targeted antibody and intracellular signaling domain, known as chimeric antigen receptor (CAR). This new area of research, referred to as adoptive T cell therapy, has recently undergone many technological advances. Importantly, T-cell therapy approaches have the potential to protect helper CD4 T cells and equip them with direct antiviral functions, which may be critical for improving HIV-specific cytotoxicity and achieving control over HIV replication in the absence of antiretroviral therapy. While major advances have already been made in the field of T cell engineering for adoptive therapy, including demonstrations of safety and feasibility, no clinical trial has resulted in durable and consistent control over HIV-replication in the absence of HAART.
In contrast to a vaccine approach, which relies on the production and priming of HIV-specific lymphocytes within a patient's own body, adoptive T-cell therapy provides an opportunity to customize the therapeutic T cells prior to administration. Thus, despite the unsuccessful therapeutic attempts using direct genetic manipulation of T cells, it is clear that adoptive cellular therapies could facilitate a functional cure by generating HIV-resistant cells, redirecting HIV-specific immune responses, or a combination of the two strategies. However, at present, it is unclear how to best engineer T cells so that sustained control over HIV replication can be achieved in the absence of antiretroviral therapy.
There is a great need in the art for more effective T-cell gene-engineering and gene-editing strategies that inhibit HIV replication and provide a gene therapy-mediated functional cure. This invention addresses this need.